MRI diagnostic procedures using tripodal pyridinyl metal complexes

ABSTRACT

A method of performing an NMR diagnostic procedure in a patient in need of the same comprising administering to the patient an effective amount of an NMR diagnostic medium and then exposing the patient to an NMR measurement step to which the diagnostic medium is responsive thereby imaging at least a portion of the patient&#39;s body, wherein the diagnostic medium comprises a composition of matter which contains a compound which has the structural formula: ##STR1## wherein R, R 1  -R 10  and M are defined herein.

FIELD OF THE INVENTION

This invention relates to magnetic resonance imaging (MRI), X-rayimaging, and radiopharmaceuticals. More particularly the inventionrelates to methods and compositions for enhancing MRI, X-ray imaging,and radiopharmaceuticals, ligands therefor and precursors of saidligands.

BACKGROUND OF THE INVENTION

The use of contrast agents in diagnostic medicine is rapidly growing. InX-ray diagnostics, for example, increased contrast of internal organs,such as the kidneys, the urinary tract, the digestive tract, thevascular system of the heart (angiography), and so forth is obtained byadministering a contrast agent which is substantially radiopaque. Inconventional proton MRI diagnostics, increased contrast of internalorgans and tissues may be obtained by administering compositionscontaining paramagnetic metal species which increase the relaxation rateof surrounding protons. In ultrasound diagnostics, improved contrast isobtained by administering compositions having acoustic impedancesdifferent than that of blood or other tissues.

The recently developed technique of MRI encompasses the detection ofcertain atomic nuclei utilizing magnetic fields and radio-frequencyradiation. It is similar in some respects to x-ray computed tomography(CT) in providing a cross-sectional display of the body organ anatomywith excellent resolution of soft tissue detail. As currently used, theimages produced constitute a map of the proton density distribution, therelaxation times, or both, in organs and tissues. The technique of MRIis advantageously non-invasive as it avoids the use of ionizingradiation.

While the phenomenon of NMR was discovered in 1945, it is only recentlythat it has found application as a means of mapping the internalstructure of the body as a result of the original suggestion ofLauterbur (Nature, 242, 190-191 ( 1973!). The fundamental lack of anyknown hazard associated with the level of magnetic and radio-frequencyfields that are employed renders it possible to make repeated scan ofvulnerable individuals. In addition to standard scan planes (axial,coronal, and sagittal), oblique scan planes can also be selected.

With an MRI experiment, the nuclei under study in a sample (e.g.protons) are irradiated with the appropriate radio-frequency (RF) energyin a highly uniform magnetic field. These nuclei, as they relax,subsequently emit RF at a sharp resonance frequency. The resonancefrequency of the nuclei depends on the applied magnetic field.

According to known principles, nuclei with appropriate spin when placedin an applied magnetic field (B, expressed generally in units of gaussor Tesla 10⁴ gauss!) align in the direction of the field. In the case ofprotons, these nuclei precess at a frequency, f, of 42.6 MHZ, at a fieldstrength of 1 Tesla. At this frequency, an RF pulse of radiation willexcite the nuclei and can be considered to tip the net magnetization ofthe field direction, the extent of this rotation being determined by thepulse duration and energy. After the RF pulse, the nuclei "relax" orreturn to equilibrium with the magnetic field, emitting radiation at theresonant frequency. The decay of the emitted radiation characterized bytwo relaxation times, i.e., T₁, the spin-lattice relaxation time orlongitudinal relaxation time, that is, the time taken by the nuclei toreturn to equilibrium along the direction the externally appliedmagnetic field, and T₂, the spin-spin relaxation time associated withdephasing of the initially coherent precession of individual protonspins. These relaxation times have been established for various fluids,organs and tissues in different species of mammals.

In MRI, scanning planes and slice thicknesses can be selected. Thisselection permits high quality transverse, coronal and sagittal imagesto be obtained directly. The absence of any moving parts in MRIequipment promotes high reliability. It is believed that MRI has agreater potential than CT for the selective examination of tissuecharacteristics in view of the fact that in CT, X-ray attenuationcoefficients alone determine image contrast, whereas at least fiveseparate variables (T₁, T₂, proton density pulse sequence and flow) maycontribute to the MRI signal.

By reason of its sensitivity to subtle physiochemical differencesbetween tissue types in detecting diseases which induce physiochemicalchanges that may not be detected by X-ray or CT which are only sensitiveto differences in the electron density of tissue.

As noted above, two of the principal imaging parameters are therelaxation times, T₁ and T₂. For protons (or other appropriate nuclei),these relaxation times are influenced by the environment of the nuclei,(e.g., viscosity, temperature, and the like). These two relaxationphenomena are essentially mechanisms whereby the initially impartedradio-frequency energy is dissipated to the surrounding environment. Therate of this energy loss or relaxation can be influenced by certainother nuclei which are paramagnetic. Chemical compounds incorporatingthese paramagnetic nuclei may substantially alter the T₁ and T₂ valuesfor nearby protons. The extent of the paramagnetic effect of a givenchemical compound is a function of the environment.

In general, paramagnetic species such as ions of elements with atomicnumber of 21 to 29, 42 to 44 and 58 to 70 have been found effective asMRI contrasting agents. Examples of suitable ions include chromium(III), manganese (II), manganese (III), iron (II), iron (III), cobalt(II), nickel (II), copper (II), praseodymium (III), neodymium (III),samarium (III), and ytterbium (III). Because of their very strongmagnetic moments, gadolinium (III), terbium (III), dysprosium (III),holmium (III) and erbium (III) are preferred. Gadolinium (III) ions havebeen particularly preferred as MRI contrasting agents.

Typically, paramagnetic ions have been administered in the form ofcomplexes with organic complexing agents. Such complexes provide theparamagnetic ion in a soluble, non-toxic form, and facilitate theirrapid clearance from the body following the imaging procedure. Gries etal., U.S. Pat. No. 4,647,447, disclose complexes of various paramagneticions with conventional aminocarboxylic acid complexing agents. Apreferred complex disclosed by Gried et al. is the complex of gadolinium(III) with diethylenetriamine-pentaacetic acid ("DTPA"). Paramagneticions, such as gadolinium (III), have been found to form strong complexeswith DTPA, ethylenediamine-tetraacetic acid ("EDTA"), and withtetraazacyclododecane-N,N',N",N"'-tetraacetic acid ("DOTA").

These complexes do not dissociate substantially in physiological aqueousfluids. The gadolinium complex of DTPA has a net charge of -2, whereasthe gadolinium complex of EDTA or DOTA has a net charge of -1, and bothare generally administered as soluble salts. Typical salts are sodiumand N-methylglucamine. The administration of salt is attended by certaindisadvantages. These salts can raise the in vivo ion concentration andcause localized disturbances in osmolality, which in turn, can lead toedema and other undesirable reactions.

Efforts have been made to design new ionic and neutral paramagneticmetals complexes which avoid or minimize the above mentioneddisadvantages. In general, this goal can be achieved by converting oneor more of the free carboxylic acid groups of the complexing agents toneutral, non-ionizable groups. For example, S. C. Quay, in U.S. Pat.Nos. 4,687,658 and 4,687,659, discloses alkylester and alkylamidederivatives, respectively, of DTPA complexes. Similarly, published Deanet al., U.S. Pat. No. 4,826,673 discloses mono- andpolyhydroxyalkylamide derivatives of DTPA and their use as complexingagents for paramagnetic ions. It can also be achieved by covalentattachment of organic cations of the complexing agent in such a mannerthat the sum of positive and negative charges in the resulting metalcomplex is zero.

The nature of additional substituents in the complexing agent can have asignificant impact on tissue specificity. Hydrophilic complexes tend toconcentrate in the interstitial fluids, whereas lipophilic complexestend to associate with cells. Thus, differences in hydrophilicity canlead to different applications of the compounds. See, for example,Weinmann et al. AJR 142, 679 (March 1984) and Brasch, et al. AJR,142,625 (March 1984).

Finally, toxicity of paramagnetic metal complexes is greatly affected bythe nature of the complexing agents. In vivo release of free metal ionsfrom the complex is a major cause of toxicity. Four principal factorsare important in the design of chelates for making paramagnetic metalcomplexes that are highly stable in vivo and less toxic. The first threefactors are thermodynamic in nature whereas the fourth involves chelatekinetics. The first factor is the thermodynamic stability constant ofthe metal-ligand. The thermodynamic stability constant indicates theaffinity that the totally unprotonated ligand has for a metal. Thesecond factor is the conditional stability constant which takes intoaccount the pH and is important when considering stability underphysiological pH. The selectivity of the ligand for the paramagneticmetal over other endogenous metal ions such as zinc, iron, magnesium andcalcium is the third factor. In addition to the three thermodynamicconsiderations, complexes with structural features that make in vivotransmetallation reactions much slower than their clearance rates wouldbe predicted to have low toxicities. Therefore, in vivo reactionkinetics are a major factor in the design of stable complexes. See, forexample, Caheris et al., Magnetic Resonance Imaging, 8:467 (1990) andOksendal, et al., JMRI, 3:157 (1993).

A need continues to exist for new and structurally diverse compounds foruse as imaging agents including ligands therefor and precursor ligands.There is a further need to develop highly stable complexes with goodrelaxivity and osmolar characteristics.

Thus, there is always a need for new and more effective agents requiringlower dosage use, lower toxicity, higher resolution and moreorgan/disease specificity.

DESCRIPTION OF THE PRIOR ART

The following prior art references are disclosed for informationalpurposes.

U.S. Pat. No. 4,001,323 discloses water-soluble non-ionizinghydroxy-containing amide derivatives of 2,4,6-triiodoisophthalic acidfor use as radiopaque materials.

U.S. Pat. No. 4,250,113 discloses new amides as X-ray contrast agents.

U.S. Pat. No. 4,396,598 discloses triiodoisophthalamide X-ray contrastagents.

U.S. Pat. No. 4,647,447 discloses new paramagnetic contrast agents.

U.S. Pat. No. 4,687,659 discloses homologs of diamide-DTPA-paramagneticcompounds as contrast agents for MR imaging.

U.S. Pat. No. 4,719,098 discloses enteral contrast medium useful fornuclear magnetic resonance.

U.S. Pat. No. 4,885,363 discloses1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecaneuseful when complexed with a paramagnetic metal atom as MR imagingagents.

U.S. Pat. No. 4,916,246 discloses paramagnetic chelates useful for NMRimaging.

U.S. Pat. No. 4,957,939 discloses sterile pharmaceutical compositions ofgadolinium chelates useful as enhancing NMR imaging.

U.S. Pat. No. 5,405,601 discloses functionalized tripodal ligands forimaging applications.

Proc. Natl. Acad. Sci. USA, Vol 93. pp 6610-6615, June 1996, MedicalSciences; Young et al. disclose gadolinium (III) texaphyrin: a tumorselective radiation sensitizer that is detectable by MRI.

H. Reimlinge, Chem. Be., 92, 970 (1995) discloses synthesis ofsubstituted pyrazoles.

Kamitori Y. et al, Heterocycles, 38 (1), 21 (1994) discloses synthesisof substituted pyrazoles.

Sauer, D. R. et al., Carbohyde Res., 241 (1993) 71 discloses synthesisof substituted pyrazoles.

Amoroso, A. J. et al, J. Chem. Soc., Chem. Comm. 1994, 2751, discloses ageneral synthesis of ligands.

Campbell, A. D. et al., Aust. J. Chem. 1971, 24, 377-83 discloses ageneral synthesis of ligands.

Kametani, T., Tetrahedron, 1970, 26, 5753 discloses a general synthesisof ligands. All of the above cited prior art and any other referencesmentioned herein are incorporated herein by reference in their entirety.

SUMMARY OF THE INVENTION

The present invention provides novel compositions of matter having theformulae: ##STR2## wherein R, R₁ -R₁₁, M and M" of formulae I, II, andIII are defined herein, for example, as MRI contrasting agents.

Compositions comprising the above formula (III) wherein M is aradioactive metal ion, a paramagnetic ion, or a metal ion capable ofabsorbing X-rays are also provided for use as radiopharmaceuticals,magnetic resonance imaging, and X-ray contrast agents, respectively.

Diagnostic compositions comprising the compounds of the invention arealso provided. Methods of performing diagnostic procedures withcompositions of the inventions are also disclosed. The methods compriseadministering to a patient an effective amount of compositions of theinvention and subjecting the patient to an imaging procedure.

DETAILED DESCRIPTION OF THE INVENTION

There is provided, in one part of the present invention, new andstructurally diverse compositions of matter having the formulae setforth above and identified as I, II, and III, and wherein:

R₁ is S or SO

R₂ -R₁₀ are each independently selected from the group consisting of

(a) R

(b) OR

(c) N(R)₂

(d) NHC(O)R

(e) COO⁻ M'

(f) C(O)N(R)₂, and

(g) SO₃ ⁻ M'

wherein R is selected from the group consisting of

(i) H

(ii) C₁ -C₂₀ alkyl

(iii) hydroxyalkyl (C₁ -C₃₀)

(iv) CH₂ CH(OH)CH₂ (O CH₂ CH(OH)CH₂)_(n) OH(n=0-10)

(v) CH₂ CH₂ (O CH₂ CH₂)_(n) OH (n=0-10)

(vi) ribose

(vii) glucose

(viii) peptide or polypeptide

(ix) PO₃ ²⁻ 2M'

and M' is Na⁺ or meglumine

R₁₁ is COR or P

M" is Li, Na or K, and

and M is a suitable metal ion such as a metal ion of the lanthanideseries having an atomic number of 57-71 or a transition metal of anatomic number of 21-29, 42, or 44.

In the above formula III, M is selected from the group consisting ofchromium (III), manganese (II), iron (III), iron (II), cobalt (II),nickel (II), copper (II), praseodymium (III), neodymium (III), samarium(III), ytterbium (III), gadolinium (III), terbium (III), dysprosium(III), holmium (III), erbium (III), lanthamium (III), gold (III), lead(II), bismuth (III), lutetium (III), and europium (III).

Examples of suitable alkyl groups for use with the invention includemethyl, ethyl, propyl, isopropyl, butyl, cyclohexyl, heptyl, and octyl.Suitable alkoxy groups include methoxy, ethoxy, propoxy, butoxy,pentoxy, hexoxy, heptoxy, and octoxy. Hydroxyalkyl groups suitable foruse with the invention include both mono and poly hydroxyalkyls such ashydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl,2,3,4-trihydroxybutyl, tris(hydroxymethyl)methyl and2-hydroxy-1-hydroxymethyl-ethyl. Suitable alkoxyalkyl groups includemethoxymethyl, 2,3-dimethoxypropyl, tris(methoxymethyl)methyl, and2-methoxy-1-methoxymethyl-ethyl.

The compositions of formula III are suitable for use with a variety ofmodalities including X-rays, magnetic resonance imaging andradiopharmaceuticals.

The functionality of the R₂ -R₁₀ groups of the compositions of formulaIII of the present inventions afford the additional capability ofderivatization to biomolecules and synthetic polymers. Biomoleculerefers to all natural and synthetic molecules that play a role inbiological systems. Biomolecules include hormones, amino acids,peptides, peptidomimetics, proteins, deoxyribonucleic acid (DNA)ribonucleic acid (RNA), lipids, albumins, polyclonal antibodies,receptor molecules, receptor binding molecules, monoclonal antibodies, afragment of monoclonal antibody and aptamers. Specific examples ofbiomolecules include insulins, prostaglandins, growth factors, liposomesand nucleic acid probes. Examples of synthetic polymers includepolylysine, arborols, dendrimers, cyclodextrins. The advantages of usingbiomolecules include enhanced tissue targeting through specificity anddelivery. Coupling of the chelating moieties to biomolecules can beaccomplished by several known methods (e.g., Krejacarek and TuckeBiochem. Biophys. Rs. Comm., 30, 581 (1977); Hantowich, et al. Science,220, 613 (1983). For example, a reactive moiety present in one of the R₂-R₁₀ groups is coupled with a second reactive group located on thebiomolecule. Typically, a nucleophilic group is reacted with anelectrophilic group to form a covalent bond between the biomolecule andthe chelate. Examples of nucleophilic groups include amines, anilines,alcohols, phenols, thiols, and hydrazines. Electrophilic group examplesinclude halides, disulfides, epoxides, maleimides, acid chlorides,anhydrides, mixed anhydrides, activated esters, imidates, isocyanatesand isothiocyanates. And finally, the compositions of formula III shouldprovide the additional advantage of being kinetically inert.

The present invention composition of formula III with one of morecentral metal ions or metal ion equivalents (M), such as paramagneticmetals praseodymium (III), neodymium (III), samarium (III), ytterbium(III) terbium (III), dysprosium (III), holmium (III), erbium (III), iron(II), iron (III), chromium(III), cobalt (II) and nickel (II) are usefulfor enhancing magnetic resonance images. While such metal ions arethemselves paramagnetic in nature and capable of altering the magneticresonance signal characteristics of body tissues, organs or fluids, theymay exhibit significant toxicity when administered in the form of ionicsalts. However, the novel composition of formula III are relativelysubstantially nontoxic and therefore useful for enhancing magneticresonance images by favorably altering relaxation times T₁ and T₂ andaffording improved contrast between normal and diseased tissues ororgans.

The preferred compositions of formula III are those formed with iron(II), iron (III), manganese (II), manganese (III), lutetium (III) andgadolinium (III) as the central metal ion or ions (M). Depending uponthe particular ligand employed and the particular central metal ion used(M), the compositions formed may be neutral, ionic, cationic, orzwitterionic in nature, or they may be negatively charged. The neutralcompositions are generally preferred and generally appear to exhibitrelatively lower toxicity as compared to ionic or negatively chargedcompositions. The negatively charged compositions formed by the ligandsand central metal ions enumerated above may be further complexed withone or more cations of an inorganic or organic base which arephysiologically tolerated. Examples of cations for further complexinginclude sodium, potassium, calcium, and salts of N-methylglucamine, andiethanolamine.

In addition to their utility in magnetic resonance imaging procedures,the compositions of formula III can also be employed for delivery ofeither radiopharmaceuticals or heavy metals for X-ray contrast into thebody. For use in diagnostic and therapeutic radiopharmaceuticals thecomplexed metal ion (M) must be radioactive. Radioisotopes of theelements technetium, rhenium, indium, gallium, copper, ytterbium,samarium and holmium are suitable. For use as X-ray contrastapplications the complexed metal ion (M) must be able to absorb adequateamounts of the X-rays. These metal ions are generally referred to asradiopaque. Suitable elements for use as the radiopague metal ioninclude lead, bismuth, gadolinium, dysprosium, holmium and praseodymium.

The compositions of formula III can be formulated into diagnosticcompositions for enteral or parenteral administration. Thesecompositions contain an effective amount of the paramagnetic ion complexalong with conventional pharmaceutical carriers and excipientsappropriate for the type of administration contemplated. For example,parenteral formulations advantageously contain a sterile aqueoussolution or suspension of from about 0.05 to about 1.0M or aparamagnetic ion complex according to this invention. Parenteralcompositions may be injected directly or mixed with a large volumeparenteral composition for systemic administration. Preferred parenteralformulations have a concentration of paramagnetic ion complex of about0.1M to about 0.5M. Such solutions also may contain pharmaceuticallyacceptable buffers and, optionally, electrolytes such as sodiumchloride. The compositions may advantageously contain a slight excess(e.g., from about 0.01 to about 15.0 mole % excess) of a complexingagent or its complex with a physiologically acceptable, nontoxiccations. Such physiologically acceptable, non-toxic cations includecalcium ions, magnesium ions, copper ions, zinc ions, salts ofn-methylglucamine and diethanolamine, and the like. Generally, calciumions are preferred.

Formulations for enteral administration may vary widely, as iswell-known in the art. In general, such formulations are liquids whichinclude an effective amount of the paramagnetic ion complex in aqueoussolution of suspension. Such enteral compositions may optionally includebuffers, surfactants, thixotropic agents, and the like. Compositions fororal administration may also contain flavoring agents and otheringredients for enhancing their organoleptic qualities.

The diagnostic compositions are administered in doses effective toachieve the desired enhancement of MR image. Such dose may vary widely,depending upon the particular paramagnetic ion complex employed, theorgans or tissues which are subject of the imaging procedure, the MRimaging procedure, the MR imaging equipment being used, and the like. Ingeneral, parenteral dosages will range from about 0.001 to about 1.0mmol of paramagnetic ion complex per kg of patient body weight.Preferred parenteral dosages generally range from about 0.01 to about0.5 mmol of paramagnetic ion complex per kg of patient body weight.Enteral dosages generally range from about 0.5 to about 100 mmol,preferable from about 1.0 to about 10.0 mmol, preferably from about 1.0to about 20.0 mmol of paramagnetic ion complex per kg of patient bodyweight.

The diagnostic compositions of the present invention are used in theconventional manner. The compositions may be administered to a patient,typically a warm-blooded animal, either systemically or locally to theorgan or tissue to be imaged, and the patient then subjected to the MRimaging procedure. Protocols for imaging and instrument procedures arefound in texts such as Stark, D. D.; Bradley, W. G. Magnetic ResonanceImaging; Mosby Year Book: St. Louis, Mo., 1992.

Radiopharmaceutical Imaging Procedures are found in Fred A. Mettler,Jr., M.D. M.P.H., Milton J. Guiberteau, M.D., Essentials of NuclearMedicine Imaging, Grune and Stratton, Inc., New York, N.T. 1983) and E.Edmund Kim, M.S., M.D. and Thomas P. Haynie, M.D., (MacMillan PublishingCo. Inc., New York, N.Y. 1987).

XRCM Imaging Procedures are found in Albert A. Moss, M.D., Gordon Gamsu,M.D., and Harry K. Genant, M.D., Computed Tomography of the Body, (W. B.Saunders Company, Philadelphia, Pa., 1992) and M. Sovak, Editor,Radiocontrast Agents, (Springer-Verlag, Berlin 1984).

In another facet of the present invention, there is provided new ligandswhich have application (after complexing with, for example, aparamagnetic ion) in the MRI area. These ligands have the generalformula set forth in II above.

In still another facet of the present invention, there is provided newprecursors (sometimes referred to as "precursors"herein) to the ligands(of formula II) and which have the general formula set forth in I above.

Examples of the type of compounds falling within formulae I, II and IIIare set forth in Table I below.

                                      TABLE 1    __________________________________________________________________________    Formula    No.  M M.sup.11              R   R.sub.1                    R.sub.2                        R.sub.3                            R.sub.4                                R.sub.5                                    R.sub.6                                        R.sub.7                                           R.sub.8                                               R.sub.9                                                   R.sub.10                                                       R.sub.11    __________________________________________________________________________    III (a)         Gd           -- H   SO                    H   H   H   H   H   H  H   H   H   --    III (b)         Lu           -- H   SO                    H   H   H   H   H   H  H   H   H   --    III (c)         Nd           -- H   S CH.sub.3                        H   H   CH.sub.3                                    H   H  CH.sub.3                                               H   H   --    III (d)         Gd           -- H   S NH.sub.2                        H   OCH.sub.3                                H   H   H  NH.sub.2                                               H   OCH.sub.3                                                       --    III (e)         Lm           -- PO.sub.3 Na.sub.2                  SO                    COONa                        COONa                            H   COONa                                    COONa                                        H  COONa                                               COONa                                                   H   --    II (a)         --           Na peptide                  SO                    H   H   H   NH.sub.2                                    H   H  H   H   NH.sub.2                                                       --    II (b)         --           Li glucose                  S OCH.sub.3                        NH.sub.2                            H   OCH.sub.3                                    NH.sub.2                                        H  OCH.sub.3                                               NH.sub.2                                                   H   --    II (c)         --           K  C.sub.2 H.sub.5                  SO                    H   H   CH.sub.3                                H   H   CH.sub.3                                           H   H   CH.sub.3                                                       --    II (d)         --           K  H   SO                    CH.sub.3                        H   H   NH.sub.2                                    H   H  COONa                                               H   H   --    I (a)         --           -- --  --                    H   H   H   H   H   H  H   H   H   COH    I (b)         --           -- --  --                    CH.sub.3                        H   OCH.sub.3                                H   NH.sub.2                                        H  COONa                                               H   H   P    I (c)         --           -- --  --                    COONa                        NH.sub.2                            H   OCH.sub.3                                    NH.sub.2                                        CH.sub.3                                           H   H   H   COCH.sub.3    __________________________________________________________________________

A class of preferred compounds has the formula ##STR3## wherein R₁ is Sor SO, and M is a metal ion of the lanthanide series having an atomicnumber 57-71 or a transition metal of an atomic number 21-29, 42 or 44.

The novel precursors, novel ligands and the novel ligand-metal complexesof the present invention are prepared from substituted aromaticheterocycles ("SAH") which are generally commercially available fromAldrich Chemical Company (Milwaukee). The SAH have the general formula:##STR4## wherein R₂ -R₁₀ are the same as defined herein and X is halogensuch as Cl, Br, and I.

When R₂, R₃ and R₄ are the same as R₇, R₈ and R₉ and/or R₈, R₉ and R₁₀,then SAH of formulae A, B, and C are the same. When A, B, and/or C aredifferent, i.e. the substituents are different, then equivalent moles ofeach must be used in order to prepare the desired precursors, ligandsand/or metal-ligand complexes. For example, when A, B, and C are all thesame, X is halogen (such as Br) and then a halogen lithium exchangereaction is carried out at low temperature (e.g. from about -100° C. toabout 20° C.) to generate a monolithium reagent, which is then coupledwith a linking reagent such as POCl₃, PCl₃, methyl chloroformate ordiphenylcarbonate to link three units of SAH to form a capping modeligand in one or two steps as shown in Schemes 1 and 2. The otherhalogen atom on the SAH is replaced in order to introduce the SH groupin one or more steps, also shown in Scheme 2.

Scheme 3 represents the situation where R₂ -R₁₀ are different, asdiscussed above with reference to formulae A, B, and C. In this case,the following general procedure is carried out.

2,6-dihalo-3-R₅ -4-R₆ -5-R₇ -pyridine (7) is slurried in diethyl etherand cooled to -70° C. One equivalent of butyllithium in hexane is addeddropwise. The resulting slurry is stirred at -70° C. until a clearsolution (9) is obtained. Transfer the resulting solution (9) through acannula to a reaction flask containing an ether solution of methyl2-halo-3-R₂ -4-R₃ -5-R₄ -picolinate (1) at -70° C. The resultingsolution is stirred at -70° C. for one hour and then allowed to warm to-10° C. when it is quenched with NH₄ Cl/H₂ O. The volume of the ether isreduced to 1/3 of the original to cause precipitation of the product(2). The precipitate is filtered and dried.

Solution (10) is generated with the same procedure as described for (9).(9) is then transferred to a flask containing an ether solution of (2)at -70° C. The resulting solution is stirred at -70° C. for one hour andthen allowed to warm to -10° C. when it is quenched with NH₄ Cl/H₂ O.The volume of the ether is reduced to 1/3 of the original to causeprecipitation of the product (3). The precipitate was filter and dried.

A one liter 3-neck schlenk flask, equipped with a stirbar, is charged(3) under nitrogen atmosphere. Anhydrous DMF is added to dissolve (3).In a beaker, sodium thiomethoxide (18 eq) is slurried with DMF. Theslurry is then slowly added to the solution of (3) with stirring. A bluesolution is obtained and it is very hot. The center neck is thenstoppered and a thermowell/adapter placed in a side neck. After sealingthe sidearm stopcock, the flask is removed from the box, and placedunder nitrogen. A reflux condenser is placed on the center neck. Thesolution is refluxed for 6-7 hours with stirring. The blue colordisappears after 1 hour. After reflux, the solution is cooled with abath and titrated to a pH of about 6 from an initial pH of >14, withconc. HCl solution. Salt is filtered and filtrate concentrated. Water isadded to break up any gummy residue to give a yellow solid, which isfiltered, washed with water and dried to yield (4) in quantitativeyield.

The mercato compounds (4) are oxidized to the sulfenate compounds (5) byoxygen in anhydrous DMF and LiOH. (4) are also oxidized to the sulfinatecompounds by forming sodium salts first with NaOH and then twoequivalents of hydrogen peroxide. ##STR5##

The final step in the overall synthesis for preparing the ligand-metalcomplex is reaction of the novel ligand with a solution containing themetal ion in the form of a compound which, for example, may be theacetate form, e.g. Gd(OAc)₃. The pressures (e.g. atmospheric) andtemperatures (e.g. 30° C. -100° C.) are suitable. The mole ratio ofligand to metal (atom) is from about 5:1 to about 4:1, preferably about1:1.

Some examples of specific processes for preparing the novel compositions(formula I, II, and III) of the present invention are set forth inSchemes 1, 2, and 3 and which, respectively, outline the detailedprocedures described in Examples 1-5.

The following specific examples are supplied for the purpose of betterillustrating the invention. These examples are not intended, however, tolimit or restrict the scope of the invention in any way and should notbe construed as providing conditions, parameters, or values which mustbe utilized exclusively in order to practice the present invention.

EXAMPLE 1

Step (a) Process for the synthesis oftris(2-bromo-6-pyridyl)methanol(TBPM) ##STR6##

Anhydrous diethylether (400 ml) and 2,6-dibromopyridine (38 g, 0.16 mol)were charged into a one-liter three-neck Schlenk flask, equipped withstirbar, a 125 ml addition funnel, a thermocouple adapter and a septum.Diphenylcarbonate (10.3 g, 0.048 mol) and diethylether (60 ml) werecharged into the addition funnel. The setup was then removed from thebox and placed under nitrogen. The flask was cooled with a -70° C.dry-ice acetone bath. When the temperature inside the flask reached -70°C., butyllithium (100 ml, 1.6M in n-hexane) was added through a cannulain such a rate that the temperature was maintained at below -70° C. Thesolution was stirred for an additional hour at -70° C. and a homogeneouslight yellow solution was obtained. Diphenylcarbonate solution was thenadded in such a rate that the temperature was maintained at -70° C. Thesolution turned into a dark purple color. Stirring was continued at -70°C. for an additional hour before the cooling bath was removed. Thesolution was quenched with ammonium chloride (9.5 g, 0.18 mol) in 30 mlof water when the temperature of the solution reached -20° C. Thesolution turned to a light brown color with precipitate, which wasfiltered and washed with water. A second batch of product was obtainedby evaporating organic solvent from the filtrate. Combined yield afterdrying was 17.5 g, 65.5%.

Step (b): Process for the synthesis oftris(2-mercapto-6-pyridyl)methanol (TMPM) ##STR7##

A 250 ml 3-neck schlenk flask, equipped with a stirbar, was charged with5 grams (0.01 mol) of tris(2-bromo-6-pyridyl) methanol (TBPM) undernitrogen atmosphere. Anhydrous DMF (100 ml) was added to dissolve TBPM.In a 250 ml beaker, sodium thiomethoxide 12.61 g. (0.1 8mol, 18eq) wasslurried with 60 ml of DMF. The slurry was then slowly added to the TBPMsolution with stirring. A blue solution was obtained and it was veryhot. The center neck was then stoppered and a thermowell/adapter placedin a side neck. After sealing the sidearm stopcock, the flask wasremoved from the box, placed under nitrogen. A reflux condenser wasplaced on the center neck. The solution was refluxed for 6-7 hours withstirring. A blue color disappeared after 1 hour. After reflux, thesolution was cooled with an ice bath and titrated to a pH of about 6from a initial pH of >14, with conc. HCl solution. Salt was filtered andfiltrate concentrated. Water (200 ml) was added to break up the gummyresidue to give a yellow solid, which was filtered, washed with waterand dried to yield 3.76 g of yellow powder. This is 104% based on theformula weight, due, most likely, to small amount of salt and solventstrapped in the solid.

EXAMPLE 2

Process for the synthesis of tris(2-mercapto-6-pyridyl)phosphine

Thiourea (2.83 g, 37.2 mmol) and tris(6-bromo-2-pyridyl)phosphine (4.99g, 9.9 mmol) were charged into a 100 ml flask equipped with nitrogenpurge, and a stir bar. Acetic acid (47 ml) was added and the slurry washeated to 60° C. to obtain a yellow solution, which was heated at 60° C.overnight. Clumps of solid was formed and filter at 60° C. The solid(about 6.0 g wet) was dissolved in 50 ml of water and the solution wasfiltered to reduce the cloudiness. NaOH (50%, 7.5 g) was added andsolution stirred at room temperature overnight. The solution was thenacidified with 6N HCl to pH 1-2, resulting precipitation of yellowsolid, which was filter and dried in a vacuum oven at 60° C. ³¹ P NMR(D₂ O, 162 MHZ), δ: -5.87. ¹ H NMR (D₂ O, 400 MHZ), δ: 5.74 (1,d,J_(H-H)=8.0 Hz); 6.94 (1,d,J_(H-H) =8.0 Hz). ¹³ C NMR (D₂ O 100 MHZ), δ:121.59; 128.94, (d, J_(C-P) =6.0 Hz); 135.72 (d, J_(C-P) =22.0 Hz);159.26 (d, J_(C-P) =8.0 Hz); 172.09 (d, J_(C-P) =15.0 Hz).

EXAMPLE 3

Synthesis of lithium tris (2-sulfenate-6-pyridyl) methanol (LiTSEPM)(n=1 in structure below) ##STR8##

Tris (2-mercapto-6-pyridyl) methanol (TMPM) (1.0 g) and 100 ml DMF werecharged into a 250 ml 2-neck flask equipped with a stirbar, a spargetube and a center 1 psi backpressure fitting. Granular LiOH (0.87 g, 13eq.) was then added and the mixture was stirred while sparging with O₂intermittently. The O₂ pressure was maintained at 1 psi above atmosphereduring sparging by the check valve mounted on the flask. After 24 hrs, aslightly yellow slurry was formed, which was decanted from remainingMOH. The slurry was filtered and the solid obtained was washed withethanol. The solid, which contained two products, the sulfenate andsulfonate in 90:10 ratios. The yield of LiTSEPM was about 50%. ¹ H NMR(400 MHz, D₂ O ) : 7.64 (3, d, J_(H-H) =8 Hz). ¹³ C NMR (100 MHz, D₂ O )δ: 82.7, 120.5, 125.9, 139.8, 158.0, 161.6, 7.83 (3,d, J_(H-H) =8 Hz),7.96 (3,t,J_(H-H) =8 Hz).

EXAMPLE 4

Synthesis of sodium tris (2-sulfinate-6-pyridyl)methanol (NaTSIPM)##STR9##

Tris (6-mercapto-6-pyridyl) methanol (0.25 g, 0.70 mmol) was chargedinto a 100 ml reaction flask equipped with a stirbar. A solution of NaOH(0.235 g) in 20 ml water/ethanol (1:1) was added. The yellow solid didnot dissolve. Hydrogen peroxide (0.4 g, 4.1 mmol) was added dropwise.Solid still did not dissolve, but color became lighter. The slurry wasstirred for 2 hours at room temperature and then evaporated under vacuumat about 65° C. to dryness. The white solid obtained, which was solublein water, was determined by NMR to be NaTSIPM. Yield, 0.43 g,quantative. ¹ H NMR (440 MHz, D₂) δ: 7.73 (6, d, J_(H-H) =4 Hz), 7.95(3, t, J_(H-H) =4 Hz). ¹³ C NMR (100 MHz, D₂ O ) δ: 83.4, 118.6, 124.2,139.1, 156.7, 165.4.

EXAMPLE 5

Synthesis of Gadolinium tris(2-sulfenate-6-pyridyl)methanol (GdTSEPM)and gadolinium tris(2-sulfinate-6-pyridyl)methanol (GdTSIPM)

LiTSEPM (0.5 g, 90%, 1.1 mmol) was dissolved in 5 ml of water and mixedwith Gd(OAc)₃. 4H₂ O (0.45 g, 1.1 mmol) in 5 ml of water. The resultingsolution was stirred at 65° C. for one hour. Volume of the solution wasreduced under vacuum to about 2 ml. solution was cooled to roomtemperature to obtain 0.3 g crystalline white powder. Yield, 48%. Theformation of the complex was followed by using capillary zoneelectrophoresis. GdTSIPM was synthesized similarly.

What is claimed is:
 1. A process of performing an MR imaging diagnosticprocedure in a patient in need of the same comprising administering tothe patient an effective amount of an MR imaging diagnostic medium andthen exposing the patient to an MR imaging measurement step to which thediagnostic medium is responsive thereby imaging at least a portion ofthe patient's body, wherein the diagnostic medium comprises acomposition of matter which contains a compound which has the structuralformula: ##STR10## wherein: M is a suitable metal ion,R₁ is S, S(O)_(n)where n is 1 R₂ -R₁₀ are each independently selected from the groupconsisting of(a) R (b) OR (c) N(R)₂ (d) NHC(O)R (e) COO⁻ M' (f)C(O)N(R)₂, and (g) SO₃ ⁻ M' wherein R is selected from the groupconsisting of(I) H (ii) C₁ -C₂₀ alkyl (iii) hydroxyalkyl (C₁ -C₃₀) (iv)CH₂ CH(OH)CH₂ (O CH₂ CH(OH)CH₂)_(n) OH (n=0-10) (v) CH₂ CH₂ (O CH₂CH₂)_(n) OH (n=0-10) (vi) ribose (vii) glucose (viii) peptide orpolypeptide, and (ix) PO₃ ²⁻ 2M'and M' is Na⁺ or meglumine.
 2. Theprocess as set forth in claim 1 wherein M is a metal ion of thelanthanide series having an atomic number of 57-71 or a transition metalof an atomic number of 21-29, 42 or
 44. 3. The process as set forth inclaim 1 wherein at least one of R₂ -R₁₀ is hydrogen.
 4. The process asset forth in claim 1 wherein at least one of R₂ -R₁₀ is CH₃.
 5. Theprocess as set forth in claim 1 wherein at least one of R₂ -R₁₀ is OCH₃.6. The process as set forth in claim 1 wherein at least one of R₂ -R₁₀is NH₂.
 7. The process as set forth in claim 1 wherein at least one ofR₂ -R₁₀ is COONa.
 8. The process as set forth in claim 1 wherein R ishydrogen.
 9. The process as set forth in claim 1 wherein R is PO₃ Na₂.10. The process as set forth in claim 1 wherein R is peptide.
 11. Theprocess as set forth in claim 1 wherein R is glucose.
 12. The process asset forth in claim 1 wherein R is C₂ H₅.
 13. The process as set forth inclaim 1 wherein M is selected from the group consisting of chromium(III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II),copper (II), praseodymium (III), neodymium (III), samarium (III),ytterbium (III), gadolinium (III), terbium (III), dysprosium (III),holmium (III), erbium (III), lanthanium (III), gold (III), lead (II),bismuth (III), lutetium (III), and europium (III).
 14. The process asset forth in claim 1 wherein M is gadolinium (III).
 15. The process asset forth in claim 1 wherein M is lutetium (III).
 16. The process as setforth in claim 1 wherein R₁ is S.
 17. The process as set forth in claim1 wherein R₁ is SO.
 18. The process as set forth in claim 1 wherein thecomposition has the formula ##STR11## wherein n is 0 or
 1. 19. Theprocess as set forth in claim 1 wherein the composition has the formula##STR12## wherein: R₁ is S or SO.M is a metal ion of the lanthanideseries having an atomic number 57-71 or a transition metal of an atomicnumber 21-29, 42 or
 44. 20. The process as set forth in claim 19 whereinM is gadolinium or lutetium.